Probing fibrils from different types of Alzheimer’s

A hallmark of Alzheimer’s disease is the accumulation of amyloid-β fibrils in the brain. It’s still an open question whether structural differences in these fibrils correlate with different subtypes of the disease such as so-called rapid-progression Alzheimer’s.

To help answer that question, Robert Tycko and coworkers at the National Institutes of Health have used brain tissue from patients with one of three forms of Alzheimer’s disease to seed the formation of fibrils in the lab. These fibrils were made from 40-residue and 42-residue amyloid-β peptides, common to the disease. Nuclear magnetic resonance spectroscopy signatures of the fibrils suggest that there may indeed be a correlation between fibril structure and disease manifestation (Nature 2017, DOI: 10.1038/nature20814).

Tycko and coworkers used brain tissue from patients with typical slow-progression Alzheimer’s, posterior cortical atrophy variant Alzheimer’s, and rapid-progression Alzheimer’s.

The NMR spectra revealed that for all disease subtypes there’s one predominant fibril structure for the Aβ-40 peptide and two predominant structures for the Aβ-42 peptide. “For the 40-residue peptide, in most cases the predominant structure seems to account for about 80% of the fibrils we derive from brain tissue,” Tycko says. In the rapid progression samples, there are signs of greater structural heterogeneity than in the other subtypes. That heterogeneity may be a contributing factor in that form of Alzheimer’s.

“It is incredibly difficult to get structural information about amyloid fibers, even for simple in vitro proteins,” says Martin T. Zanni, a chemistry professor at the University of Wisconsin, Madison, who studies amyloid formation. “It looks like Tycko has discovered the most important (or at least more predominant) polymorph—the one we should all be studying.”

But Tycko cautions that they don’t yet know the three-dimensional structure of the predominant form. “We found the NMR signatures for certain structures. We don’t actually know what the 3-D structures look like and how different they are from structures that have been determined before,” Tycko says. “We’re now trying to figure out what those structures really are.”